Project Summary/Abstract Investigations in humans and animal models show maladaptive brain pathologies that are a consequence of repeated drug use. Neuroimaging studies show that specific regions of the prefrontal cortex (PFC), critical for cognitive processing, are dampened (i.e., become ?offline?) in human addicts. Given the critical role of the PFC in cognition, and its anatomic link to brain ?reward? structures such as the nucleus accumbens (NAc), the inability to abstain from drug taking may stem in part from deficits in associative learning induced by the drug. Rodent studies support this view. For example, research in the Carelli lab has revealed that rats with a history of cocaine self-administration are able to learn first-order (Pavlovian) associations, but are then unable to use that information to flexibly alter habitual actions. Critically, these deficits in behavior are linked to decreases in neural signaling in the prelimbic (PrL) cortex and NAc core during first order conditioning that may underlie the subsequent cocaine-induced deficits in behavioral flexibility. Thus, one effective treatment strategy for addiction may be to ?restore? alterations in neural signaling in the PFC and associated regions that are a consequence of repeated drug use. One innovative approach that holds great promise in this regard is Non-Invasive Brain Stimulation (NIBS). Indeed, recent data indicates that NIBS that targets PFC regions in human addicts can modulate cortical excitability, and dampen drug craving. Recently, working in collaboration with an expert in NIBS, we developed a rat model of one form of NIBS, transcranial alternating current stimulation (tACS). Here, exogenous electric fields resulting from tACS can be used to modulate cortical oscillations in brain (for example, those that are disrupted following a history of cocaine) by simply applying mild alternating electrical currents to the skull. While NIBS such as tACS holds great promise, virtually no information is known about how it can modulate neural systems to reverse cocaine-induced deficits, since rodent models of this approach are lacking. Therefore, the overall goal of this exploratory R21 application is to apply our tACS approach in combination with our well-established electrophysiology methods (spike and local field potential) to examine if tACS can ?re-adjust? neural signaling in the PrL and NAc core and ameliorate cocaine-induced deficits in flexible behaviors. Aim 1 will determine if tACS can reverse cocaine-induced alterations in flexible behavior and associated shifts in neural encoding in PrL and NAc core in male rats. Aim 2 will determine if tACS reverses cocaine-induced alterations in flexible behavior and associated shifts in neural encoding in the PrL and NAc core in female rats; estrous cycle will be also tracked to determine if it is related to behavioral flexibly and tACS actions. This application is highly innovative in that it will provide novel insight into how tACS can modulate neural signaling and cocaine-induced deficits in associative learning across sexes, and, since this approach is ?noninvasive? (i.e., electrical stimulation is applied to screws mounted on the skull, not in brain), holds great translational value.